US3655885A - Antibacterial compositions and methods of treating bacterial infections - Google Patents

Antibacterial compositions and methods of treating bacterial infections Download PDF

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US3655885A
US3655885A US48827A US3655885DA US3655885A US 3655885 A US3655885 A US 3655885A US 48827 A US48827 A US 48827A US 3655885D A US3655885D A US 3655885DA US 3655885 A US3655885 A US 3655885A
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acid
deoxy
lincomycin
chloro
hydrochloride
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Walter Morozowich
Anthony A Sinkula
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof

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  • the novel compounds of the invention are represented by Formula I, wherein is a carboxylic acid acyl radical, advantageously a hydrocarbon carboxylic acid acyl of not more than 18 carbon atoms; or a halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or loweralkoxy-substituted hydrocarbon carboxylic acid acyl radical advantageously of not more than 18 carbon atoms, X is chlorine, or bromine; R, and HR are the same or diflerent alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms, advantageously not more than 8 carbon atoms; and R is hydrogen, alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl of not more
  • alkyl of not more than 20 carbon atoms examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl and the isomeric forms thereof.
  • cycle alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Z-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4-methy1- cyclobutyl, and 3-cyclopentylpropyl.
  • aralkyl examples include benzyl, phenethyl, a-phenylpropyl, and m-naphthylmethyl.
  • carboxylic acid acyl radicals are the acyl radicals of the following acids: (a) saturated or un- Patented Apr.
  • Suitable halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, and lower alkoxyhydrocarbon carboxylic acids include hydrocarbon carboxylic acids as given above which are substituted by one or more of halogen, nitro, hydroxy, amino, cyano, or thiocyano, or loweralkoxy, advantageously loweralkoxy of not more than 18 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, amyloxy, hexyloxy, and isomeric forms thereof.
  • Examples of such substituted hydrocarbon carboxylic acids are "ice monomono-, di-, and trichloracetic acid;
  • homogentisic acid o-, m-, and p-chlorobenzoic acid; anisic acid; salicyclic acid; p-hydroxybenzoic acid; fi-resorcylic acid; gallic acid; veratric acid; trimethoxybenzoic acid; trimethoxycinnamic acid; 4,4'-dichlorobenzilic acid; 0-, m-, and p-nitrobenzoic acid; cyanoacetic acid; 3,4- and 3,5-dinitrobenzoic acid; 2,4,6-trinitrobenzoic acid; thiocyanoacetic acid; cyano propionic acid; lactic acid; ethoxyformic acid (ethyl hydrogen carbonate); butyloxyformic acid; pentyloxyformic acid; hexyloxyformic acid; dodecyloxyformic acid; hexadecyloxyformic acid, and the like.
  • the compounds of the invention have essentially the same antibacterial spectrum in vivo as the antibiotic lincomycin and can be used for the same purposes as lincomycin.
  • the compounds of the invention are more active 3 and can advantageously be used for oral administration to animals, including mammals.
  • novel compounds of this invention are prepared by condensing a 7-halo-7-deoxy-lincomycin of the formula:
  • R When R is hydrogen it is replaced by a protective group before acylation.
  • this group is a protective group removable by hydrogenolysis. Suitable such groups are carbobenzoxy and like hydrocarbonoxycarbonyl groups, benzyl, and nitrobenzyl.
  • a 7-halo-7-deoxy-lincomycin of Formula II is first condensed with an aromatic aldehyde, with the aid of mild heat, to form a 3,4-O-arylidene 7-halo-7-deoxy-lincomycin of Formula III. Acid catalysis of the reaction is unnecessary if the hydrochloride salt of the 7-halo-7-deoxy-lincomycin is used as this provides sufficient catalysis of the reaction.
  • reaction mixture When the hydrogen group at position 1 is substituted by a protective group which renders the molecule non-basic, e.g., by a carbobenzoxy group, it is advantageous to supplement reaction mixture with catalytic amounts of mineral acids or, preferably, of acidic salts such as ammonium chloride, to facilitate the condensation reaction.
  • the reaction is forced to completion through azeotropic removal of water by an organic solvent, for example, benzene, toluene, chloroform, ethylene chloride, and the like.
  • the azeotrope-forming solvent can be eliminated if water is removed by some other means, such as by evacuation, vaporization with an inert gas, or merely by co- '4 distillation with a solvent which has a higher boiling point than water.
  • the azeotrope-forming solvent is used in admixture with a highly polar solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, and the like, in order to solubilize 7-halo-7-deoxy-lincomycin hydrochloride and thus produce a homogeneous solution.
  • a highly polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, and the like
  • the condensation reaction can be conducted between temperatures of about 70 to 180 C.; the preferred temperature being about -110 C.
  • the optimum temperature depends on the ratio of polar to non-polar solvent, and on the specific properties of the non-polar solvent, such as the boiling temperature of the azeotrope formed with water as Well as the boiling point of the non-polar solvent itself.
  • the non-polar solvent containing moisture can be continuously removed by distillation and replaced periodically with fresh, dry solvent.
  • the water also can be removed by condensation and separation with a water trap or a dessicant can be used, thus permitting the dried solvent to return to the reaction vessel.
  • the time for complete condensation of the 7-halo-7- deoxy-lincomycin hydrochloride with an aromatic aldehyde varies with the solvent composition, and the efficiency of removal of the water.
  • azeotrope-forming solvents as described above, the course of the reaction can be followed by measuring the amount of water liberated.
  • the reaction vessel can be sampled periodically and chromatographed. With solvent combinations of benzene and dimethylformamide, reaction times of about 1-16 hours can be used, with 2-3 hours being optimum.
  • aromatic aldehydes can be used in the process of the invention, for example, furfural, S-methylfurfural, 'benzaldehyde, salicylaldehyde, m-tolualdehyde, o-tolualdehyde, p-tolualdehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, m-methoxybenz'aldehyde, o methoxybenzaldehyde, 3,4 dimethoxybenzaldehyde (veratric aldehyde), salicylaldehyde phydroxy benzaldehyde, 3,4,5 trimethoxybenzaldehyde, piperonal, o-nitrobe'nzaldehyde, p chlorobenzaldeh
  • aldehydes in which the carbonyl group is separated from the aromatic moiety by one or more double bonds giving a conjugated structure of:
  • n can be an integer of from 1-4
  • Z can be one of the following substituents on the aromatic moiety:
  • deoxy-lincomycin, and 3,4-p-chlorobenzylidene-7-halo-7- deoxy-lincomycin recrystallization of the hydrochlorides can be brought about with hot methyl Cellosolve, dimethylformamide, chloroform, and the like.
  • the less stable acetals for example, 3,4-p-anisylidene-7-halo-7-deoxylincomycin, 3,4-cinnamylidene, and 3,4-toluylidene-7- halo-7-deoxy-1incomycin, must be converted to the free base from before isolation of the acetal.
  • the 3,4 O-aryIidene-7-haIo-7-deoxy-lincomycin hydrochloride salts are usually of a high degree of purity and can be used in acylation as such or they can be converted to the free base by mixing the salts with a basic material, for example, aqueous sodium hydroxide, a quaternary ammonium hydroxide, ammonium hydroxide, or a strong amine base.
  • Basic ion exchange resin can be used.
  • the insoluble arylidene-7-halo-7-deoxy-lincomycin base can be removed by filtration, or it can be extracted with waterimmiscible solvents, for example, chloroform, methylene chloride, ethylene dichloride, ether and the like.
  • the 3,4-O-arylidene-7-halo-7-deoxy-lincomycin hydrochloride salts can be converted to the free base by first neutralizing the salt with a base after placing the salt in solution in a solvent such as chloroform, dimethylformamide, dimethylacetamide, propylene glycol, and the like.
  • the base can be an alkoxide, an amine, ammonia, or a solid inorganic base, for example, sodium hydroxide, potassium hydroxide, and the like.
  • the resulting solutions of the 3,4-O-arylidene-7-halo-7-deoxy-lincomycin base can be recovered from Water-miscible solvents by dilution with water to the cloud point resulting in slow crystallization of the acetals.
  • the solutions of 3,4-O-arylidene-7- halo-7-deoxy-lincomycin base in water-immiscible solvents can be recovered by dilution of the solution with a nonpolar solvent, for example, hexane, isomeric hexanes, and the like, or by simply evaporating the solvent.
  • the 3,4-0-arylidene-7-halo-7-deoxy-lincomycin can be acylated by processes already well known in the art, for example, by reacting it with an acylating agent in the presence of an acid-binding agent, for example, a tertiary amine, to produce a 3,4-O-arylidene-7-halo-7-deoxy-lincomycin-2-acylate.
  • Suitable acylating agents include acid halides and acid anhydrides.
  • Suitable tertiary amines include heterocyclic amines such as pyridine, quinoline, and isoquinoline; trialkylamines such as trimethylamine, triethylamine, triisopropylarnine, and the like; N,N-dialkylanilines such as dimethylaniline, diethylaniline, and the like; and N-alkylpiperidines such as N-ethylpiperidine, N- methylpiperidine, and the like.
  • the preferred base is pyridine.
  • the acylation is advantageously conducted by treating a solution of a 3,4-O-arylidene-7-halo-7-deoxy-lincomycin or a suspension of the hydrochloride in a mixture of an inert solvent and a tertiary amine, for example, pyridine,
  • acylating agent for example, acyl chloride
  • the reaction is conducted in pyridine at low temperature, preferably 20 to 0., however higher or lower temperatures can be used.
  • Suitable inert solvents include chloroform, dimethylformamide, dimethylacetamide, acetonitrile, methylene chloride, acetone, and dioxane.
  • the 3,4-O-arylidene protective group can be removed by hydrolysis, preferably, a mild acid hydrolysis.
  • hydrolysis preferably, a mild acid hydrolysis.
  • 3,4-O-anisylidene-7-chloro-7-deoxy-lincomycin-2- acylate on being heated with 80% acetic acid at C. for 10 to 15 min. yields 7-chloro-7-deoxy-lincomycin-2- acylate.
  • Acids such as formic, propionic, dilute hydrochloric and dilute sulfuric can also be used.
  • the protective group Q can be removed by hydrogenolysis over a palladium catalyst.
  • a 3,4-O-anisylidene-7-chloro-7-deoxy-N-carbobenzoxy-lincomycin-2 acylate is hydrogenated using palladium as catalyst.
  • the hydrogenolysis also removes the 3,4-O-anisylidene group.
  • the palladium is usually deposited on a carrier, for example, carbon.
  • the hydrogenolysis advantageously, is effected in a solvent at a temperature between about 10 C. and 50 C., and at a pressure not above about 60 lbs. per square inch gauge. Suitable solvents include methanol, acetic acid, ethylacetate, chloroform, and dioxane. v
  • the desired 2-acylate can be isolated from the reaction mixture by various techniques well known in the art.
  • the 2-acylates so prepared are easily isolated as the hydrochloride salt by precipitation with a non-solvent such as acetone or ether.
  • the compounds are usually isolated in a pure state by this method although if necessary recrystallization may be achieved from water or acetone plus a small amount of water.
  • novel compounds of the invention are nitrogenous bases and can exist in a protonated or a non-protonated form according to the pH of the environment.
  • the protonated form is intended the compound is qualified as the acid addition salt; when the non-protonated form is intended it is qualified as the free base.
  • the free bases can be converted to stable acid-addition salts by neutralizing the free base with the appropriate acid to below about pH 6.0 and advantageously to about pH 2 to pH 6.
  • Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic,
  • the acid-addition salts can be used for the same purposes as the free base or they can be employed to upgrade the same.
  • the free base can be converted to an insoluble salt, such as the picrate, which can be subjected to purification procedures, for example, solvent extractions and washings, chromatography, fractional liquid-liquid extractions, and crystallization and then used to regenerate the free base form by treatment with alkali or to make a different salt by metathesis.
  • the free base can be converted to a water-soluble salt, such as the hydrochloride or sulfate and the aqueous solution of the salt extracted with various Water-immiscible solvents before regenerating the free base form by treatment of the thus-extracted acid solution or converted to another salt by metathesis.
  • the free bases can be used as a buffer or as an antacid. They also react with isocyanates to form urethanes and can be used to modify polyurethane resins.
  • the long chain compounds i.e., where HR is alkyl of from 8 carbon atoms up, have surface active properties and can be used as wetting and emulsifying agents.
  • the thiocyanic acid addition salt when condensed with formaldehyde forms resinous materials useful as inhibitors according to US. Pats. 2,425,320 and 2,606,155 in the acid pickling of steel.
  • the free bases also make good vehicles for toxic acids.
  • the fluosilicic acid addition salts are useful as mothproofing agents according to US. Pats. 1,915,334 and 2,075,359, and the hexafluoroarsenic acid and hexafluorophosphoric acid addition salts are useful as parasiticides according to US Pats. 3,122,536 and 3,122,552.
  • the free bases also form salts with penicillins. These salts retain the antibacterial activity of the penicillins but have different solubility characteristics which make them useful in situations indicated by the special solubility characteristics and in the isolation and purification of the penicillins, particularly benzyl penicillin. Said salts can be formed either by neutralization of the free base form of a compound with the free acid form of a penicillin, or by a metathetical exchange of the anion of an acid "addition salt of the compound, for example, the chloride ion of a hydrochloride, with the anionic form of a penicillin.
  • the starting 7-halo-7-deoxy-lincomycins of Formula II can be prepared by reacting the corresponding lincomycin with thionyl chloride (Belgian Pat. 676,154) or with a Rydon reagent (Belgian Pat. 676,154).
  • reaction vessel was cooled and a small amount of 7(S) chloro 7 deoxy lincomycin hydrochloride was removed by filtration.
  • the filtrate was diluted with ;ether to precipitate 7.4 g. of 3,4-O-p-acetamidobenzylidene- 7(S)-chloro7-deoxy-lincornycin hydrochloride.
  • EXAMPLE 5 By substituting the 7(S)-chloro-7-deoxy-lincomycin of Examples 1, 2, and 3 by 7(S)-chloro-7-deoxy-N-carbobenzoxy-lincomycin there are obtained 3,4-'Oanisylidene- 7(S) chloro 7 deoxy N .carbobenzoxy-lincomycin, 3,4 O anisylidene 7 (S) chloro 7 deoxy N-carbobenzoxy-lincomycin-Z-palmitate, 2-laurate, and 2-hexanoate, 7(S)-chloro-7-deoxy-N-carbobenzoxy-lincomycin- 2 palmitate, 2 laurate, and 2 hexanoate.
  • EXAMPLE 7 Syrup An aqueous oral preparation containing 400 mg. of 7(S) chloro 7 deoxy lincomycin-Z-palmitate hydrochloride in each five milliliters is prepared from the following ingredients:
  • the final preparation should be adjusted to pH 4.0-4.5.
  • R and HR are the same or different alkyl of not more than 20 carbon atorn's,'cycloalkyl of from 3 to not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms; and R ishydrogen, alkyl of not more than 20 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl of not more than 12 carbon atoms, and
  • a process for control of lincomycin susceptible bacteria in animals which comprises orally administering to said animal an antibacterially elfective amount of a compound of the formula:
  • CH3 RI 5 is palmitoyl

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Abstract

ANTIBACTERIAL COMPOUNDS OF THE FORMULA:

2-(R-S-),3-(R2-COO-),4,5-DI(HO-),6-((1-R3,3-HR1-

TETRAHYDRO-1H-PYRROL-2-YL)-NH-CH(-CH(-X)-CH3)-)-

TETRAHYDROPYRAN

AND THE SALTS THEREOF, AND THE 3,4-O-ARYLIDENE DERIVATIVES.

Description

United States Patent US. Cl. 424181 Claims ABSTRACT OF THE DISCLOSURE Antibacterial compounds of the formula:
and the salts thereof, and the 3,4-O-arylidene derivatives.
CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of application Ser. No. 751,067, now abandoned, which in turn is a division of application Ser. No. 637,358, filed May 10, 1967, now abandoned.
BRIEF SUMMARY OF THE INVENTION The novel compounds of the invention are represented by Formula I, wherein is a carboxylic acid acyl radical, advantageously a hydrocarbon carboxylic acid acyl of not more than 18 carbon atoms; or a halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or loweralkoxy-substituted hydrocarbon carboxylic acid acyl radical advantageously of not more than 18 carbon atoms, X is chlorine, or bromine; R, and HR are the same or diflerent alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms, advantageously not more than 8 carbon atoms; and R is hydrogen, alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl of not more than 12 carbon atoms, advantageously not more than 8 carbon atoms.
Examples of alkyl of not more than 20 carbon atoms (R, HR and R are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl and the isomeric forms thereof. Examples of cycle alkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Z-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4-methy1- cyclobutyl, and 3-cyclopentylpropyl. Examples of aralkyl are benzyl, phenethyl, a-phenylpropyl, and m-naphthylmethyl. Example of carboxylic acid acyl radicals are the acyl radicals of the following acids: (a) saturated or un- Patented Apr. 11, 1972 saturated, straight or branched chain aliphatic carboxylic acids, for example acetic, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, lauric, tridecoic, myristic, pentadecanoic, palmitic, margaric, stearic, acrylic, crotonic, undecylenic, oleic, hexynoic, heptynoic, octynoic acids, and the like; (b) saturated or unsaturated, alicyclic carboxylic acids, for example, cyclobutane-carboxylic acid, cyclopentanecarboxylic acid, cyclopentenecarboxylic acid, methylcyclopentene carboxylic acid, cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid, dipropylcyclohexanecarboxylic acid, and the like; (c) saturated or unsaturated, alicyclic aliphatic carboxylic acids, for example, cyclopentaneacetic acid, cyclopentanepropionic acid, cyclopentaneacetice acid, cyclohexanebutyric acid, methylcyclohexaneacetic acid, and the like; (d) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid, and the like; and (e) aromatic-aliphatic carboxylic acids, for example, phenylacetic acid, phenylpropionic acid, phenylvaleric acid, cinnamic acid, phenylpropiolic acid and naphthylacetic acid, and the like. Suitable halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, and lower alkoxyhydrocarbon carboxylic acids include hydrocarbon carboxylic acids as given above which are substituted by one or more of halogen, nitro, hydroxy, amino, cyano, or thiocyano, or loweralkoxy, advantageously loweralkoxy of not more than 18 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, amyloxy, hexyloxy, and isomeric forms thereof. Examples of such substituted hydrocarbon carboxylic acids are "ice monomono-, di-, and trichloracetic acid;
aand j3-chloropropionic acid;
uand 'y-bromobutyric acid;
uand iodovaleric acid;
mevalonic acid;
2- and 4-ch1orocyclohexanecarboxylic acid;
shikimic acid; Z-m'tro-l-methyl-cyclobutanecarboxylic acid; 1,2,3,4,5,6-hexachlorocyclohexanecarboxylic acid; 3-bromo-Z-methylcyclohexanecarboxylic acid;
4- and 5-bromo-2-methylcyclohexanecarboxylic acid; 5- and 6-bromo-2-methylcyclohexanecarboxylic acid; 2,3-dibromo-Z-methyl-cyclohexanecarboxylic acid; 2,5-dibromo-2-methylcyclohexanecarboxylic acid; 4,S-dibromo-2-methylcyclohexanecarboxylic acid; 5,6-dibromo-2-methy1cyclohexanecarboxylic acid; 3-bromo-3-methylcyclohexanecarboxylic acid; 6-bromo-3-methylcyclohexanecarboxylic acid; 1,6-dibromo-3 methylcyclohexanecarboxylic acid; 2-br0mo-4-methylcyclohexanecarboxylic acid; 1,2-dibromo-4-methylcyclohexanecarboxylic acid; 3-bromo-2,2,3-trimethylcyclopentanecarboxylic acid; 1-bromo-3,5-dimethylcyclohexanecarboxylic acid;
homogentisic acid, o-, m-, and p-chlorobenzoic acid; anisic acid; salicyclic acid; p-hydroxybenzoic acid; fi-resorcylic acid; gallic acid; veratric acid; trimethoxybenzoic acid; trimethoxycinnamic acid; 4,4'-dichlorobenzilic acid; 0-, m-, and p-nitrobenzoic acid; cyanoacetic acid; 3,4- and 3,5-dinitrobenzoic acid; 2,4,6-trinitrobenzoic acid; thiocyanoacetic acid; cyano propionic acid; lactic acid; ethoxyformic acid (ethyl hydrogen carbonate); butyloxyformic acid; pentyloxyformic acid; hexyloxyformic acid; dodecyloxyformic acid; hexadecyloxyformic acid, and the like.
The compounds of the invention have essentially the same antibacterial spectrum in vivo as the antibiotic lincomycin and can be used for the same purposes as lincomycin. The compounds of the invention are more active 3 and can advantageously be used for oral administration to animals, including mammals.
The novel compounds of this invention are prepared by condensing a 7-halo-7-deoxy-lincomycin of the formula:
H3 KI) x c-- NH HR HC OH III wherein Ar is aryl, acylating this compound to form a 3,4-O-arylidene 7 halo 7 deoxy lincomycin 2- acylate of the formula:
IV and removing the protective groups to form a lincomycin- Z-acylate of Formula I.
When R is hydrogen it is replaced by a protective group before acylation. Advantageously this group is a protective group removable by hydrogenolysis. Suitable such groups are carbobenzoxy and like hydrocarbonoxycarbonyl groups, benzyl, and nitrobenzyl.
In carrying out the process of the subject invention, a 7-halo-7-deoxy-lincomycin of Formula II, advantageously as the hydrochloride salt, is first condensed with an aromatic aldehyde, with the aid of mild heat, to form a 3,4-O-arylidene 7-halo-7-deoxy-lincomycin of Formula III. Acid catalysis of the reaction is unnecessary if the hydrochloride salt of the 7-halo-7-deoxy-lincomycin is used as this provides sufficient catalysis of the reaction. When the hydrogen group at position 1 is substituted by a protective group which renders the molecule non-basic, e.g., by a carbobenzoxy group, it is advantageous to supplement reaction mixture with catalytic amounts of mineral acids or, preferably, of acidic salts such as ammonium chloride, to facilitate the condensation reaction. The reaction is forced to completion through azeotropic removal of water by an organic solvent, for example, benzene, toluene, chloroform, ethylene chloride, and the like. The azeotrope-forming solvent can be eliminated if water is removed by some other means, such as by evacuation, vaporization with an inert gas, or merely by co- '4 distillation with a solvent which has a higher boiling point than water. The azeotrope-forming solvent is used in admixture with a highly polar solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, and the like, in order to solubilize 7-halo-7-deoxy-lincomycin hydrochloride and thus produce a homogeneous solution.
The condensation reaction can be conducted between temperatures of about 70 to 180 C.; the preferred temperature being about -110 C. The optimum temperature depends on the ratio of polar to non-polar solvent, and on the specific properties of the non-polar solvent, such as the boiling temperature of the azeotrope formed with water as Well as the boiling point of the non-polar solvent itself. The non-polar solvent containing moisture can be continuously removed by distillation and replaced periodically with fresh, dry solvent. The water also can be removed by condensation and separation with a water trap or a dessicant can be used, thus permitting the dried solvent to return to the reaction vessel.
The time for complete condensation of the 7-halo-7- deoxy-lincomycin hydrochloride with an aromatic aldehyde, as disclosed above, varies with the solvent composition, and the efficiency of removal of the water. When azeotrope-forming solvents are used, as described above, the course of the reaction can be followed by measuring the amount of water liberated. Alternatively, the reaction vessel can be sampled periodically and chromatographed. With solvent combinations of benzene and dimethylformamide, reaction times of about 1-16 hours can be used, with 2-3 hours being optimum. I f anhydrous 7-halo-7- deoxy-lincomycin hydrochloride is used, the reaction time required is reduced by approximately a factor of /2 since only one-half of the amount of water is liberated, compared with 7-halo 7 deoxy-lincomycin hydrochloride monohydrate. A variety of aromatic aldehydes can be used in the process of the invention, for example, furfural, S-methylfurfural, 'benzaldehyde, salicylaldehyde, m-tolualdehyde, o-tolualdehyde, p-tolualdehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, m-methoxybenz'aldehyde, o methoxybenzaldehyde, 3,4 dimethoxybenzaldehyde (veratric aldehyde), salicylaldehyde phydroxy benzaldehyde, 3,4,5 trimethoxybenzaldehyde, piperonal, o-nitrobe'nzaldehyde, p chlorobenzaldehyde, phthaldehyde, -m-nitrobenbaldehyde, p-nitrobenzaldehyde, fl-n aphthaldehyde, p-bromobenzaldehyde, o-bromobenzaldehyde, 2,4 dichlorobenzaldehyde, vanillin, methaldehyde, terephthaldehyde, protocatechualdehyde, and cinnamaldehyde.
Also useful are aldehydes in which the carbonyl group is separated from the aromatic moiety by one or more double bonds giving a conjugated structure of:
0 @(cn; ow -cf wherein n can be an integer of from 1-4, and Z can be one of the following substituents on the aromatic moiety:
CH N0 OHgOHg' O CH CH 3)z 3)2 s)3 2)3 3 PC 11 0 (CH CH ASOgH 0C6H5 ocn ococH OC H OH 3,4(CH SCI-I 0P SCH (CH 2 CN SH COCH SCOCH CO C H SCN co n socH COz SO2CH3 CH Si (CH 3 SO NH The acetals formed by the above-disclosed process are initially isolated as crystalline hydrochloride salts. With stable acetals, for example, 3,4-benzylidene-7-halo-7-.
deoxy-lincomycin, and 3,4-p-chlorobenzylidene-7-halo-7- deoxy-lincomycin, recrystallization of the hydrochlorides can be brought about with hot methyl Cellosolve, dimethylformamide, chloroform, and the like. The less stable acetals, for example, 3,4-p-anisylidene-7-halo-7-deoxylincomycin, 3,4-cinnamylidene, and 3,4-toluylidene-7- halo-7-deoxy-1incomycin, must be converted to the free base from before isolation of the acetal.
The 3,4 O-aryIidene-7-haIo-7-deoxy-lincomycin hydrochloride salts are usually of a high degree of purity and can be used in acylation as such or they can be converted to the free base by mixing the salts with a basic material, for example, aqueous sodium hydroxide, a quaternary ammonium hydroxide, ammonium hydroxide, or a strong amine base. Basic ion exchange resin can be used. The insoluble arylidene-7-halo-7-deoxy-lincomycin base can be removed by filtration, or it can be extracted with waterimmiscible solvents, for example, chloroform, methylene chloride, ethylene dichloride, ether and the like. Alternatively, the 3,4-O-arylidene-7-halo-7-deoxy-lincomycin hydrochloride salts can be converted to the free base by first neutralizing the salt with a base after placing the salt in solution in a solvent such as chloroform, dimethylformamide, dimethylacetamide, propylene glycol, and the like. The base can be an alkoxide, an amine, ammonia, or a solid inorganic base, for example, sodium hydroxide, potassium hydroxide, and the like. The resulting solutions of the 3,4-O-arylidene-7-halo-7-deoxy-lincomycin base can be recovered from Water-miscible solvents by dilution with water to the cloud point resulting in slow crystallization of the acetals. The solutions of 3,4-O-arylidene-7- halo-7-deoxy-lincomycin base in water-immiscible solvents can be recovered by dilution of the solution with a nonpolar solvent, for example, hexane, isomeric hexanes, and the like, or by simply evaporating the solvent. The latter procedure for forming the free base from the 3,4O-arylidene-7-halo-7-deoxy-lincomycin hydrochloride salts is suitable for isolating the very labile acetals of 7-halo-7-deoxylincomycin, since a nonaqueous procedure can be employed.
' Most of the 3,4--arylidene-7-halo-7-deoxy-lincomycin bases can be purified by solution of the compound in acetone, diluting the solution with ether, and then adding hexane to the cloud point to induce spontaneous crystallization.
The 3,4-0-arylidene-7-halo-7-deoxy-lincomycin can be acylated by processes already well known in the art, for example, by reacting it with an acylating agent in the presence of an acid-binding agent, for example, a tertiary amine, to produce a 3,4-O-arylidene-7-halo-7-deoxy-lincomycin-2-acylate. Suitable acylating agents include acid halides and acid anhydrides. Suitable tertiary amines include heterocyclic amines such as pyridine, quinoline, and isoquinoline; trialkylamines such as trimethylamine, triethylamine, triisopropylarnine, and the like; N,N-dialkylanilines such as dimethylaniline, diethylaniline, and the like; and N-alkylpiperidines such as N-ethylpiperidine, N- methylpiperidine, and the like. The preferred base is pyridine.
The acylation is advantageously conducted by treating a solution of a 3,4-O-arylidene-7-halo-7-deoxy-lincomycin or a suspension of the hydrochloride in a mixture of an inert solvent and a tertiary amine, for example, pyridine,
with an acylating agent, for example, acyl chloride, and cooling the reaction mixture to prevent side reactions. Advantageously, the reaction is conducted in pyridine at low temperature, preferably 20 to 0., however higher or lower temperatures can be used. Suitable inert solvents include chloroform, dimethylformamide, dimethylacetamide, acetonitrile, methylene chloride, acetone, and dioxane.
The 3,4-O-arylidene protective group can be removed by hydrolysis, preferably, a mild acid hydrolysis. For example, 3,4-O-anisylidene-7-chloro-7-deoxy-lincomycin-2- acylate on being heated with 80% acetic acid at C. for 10 to 15 min. yields 7-chloro-7-deoxy-lincomycin-2- acylate. Acids such as formic, propionic, dilute hydrochloric and dilute sulfuric can also be used.
The protective group Q can be removed by hydrogenolysis over a palladium catalyst. For example, a 3,4-O-anisylidene-7-chloro-7-deoxy-N-carbobenzoxy-lincomycin-2 acylate, either before or after the hydrolytic removal of the 3,4-O-anisylidene group, is hydrogenated using palladium as catalyst. The hydrogenolysis also removes the 3,4-O-anisylidene group. The palladium is usually deposited on a carrier, for example, carbon. The hydrogenolysis, advantageously, is effected in a solvent at a temperature between about 10 C. and 50 C., and at a pressure not above about 60 lbs. per square inch gauge. Suitable solvents include methanol, acetic acid, ethylacetate, chloroform, and dioxane. v
The desired 2-acylate can be isolated from the reaction mixture by various techniques well known in the art. The 2-acylates so prepared are easily isolated as the hydrochloride salt by precipitation with a non-solvent such as acetone or ether. The compounds are usually isolated in a pure state by this method although if necessary recrystallization may be achieved from water or acetone plus a small amount of water.
ONH
H (3, l-0-Aryl idene -7(S)- chloro-7-deoxy-l incomyci n) (7(S)-Chloro -7-deoxy-. lincomyci n-2-acylate) The novel compounds of the invention are nitrogenous bases and can exist in a protonated or a non-protonated form according to the pH of the environment. When the protonated form is intended the compound is qualified as the acid addition salt; when the non-protonated form is intended it is qualified as the free base. The free bases can be converted to stable acid-addition salts by neutralizing the free base with the appropriate acid to below about pH 6.0 and advantageously to about pH 2 to pH 6. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic,
hexafluoroarsenic, hexafluorophosphoric, acetic, succinic,-
citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, 3-phenylsalicylic, 5-phenylsalicylic, 3-methylglutaric, orthosulfobenzoic, cyclopentanepropionic, 1,2 cyclohexanedicarboxylic, 4-cyclohexanecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, dimethyldithiocarbamic, cyclohexylsulfamic, hexadecylsulfamic, octadecylsulfamic, sorbic, monochloroacetic, undecylenic, 4'-hydroxyazobenzene 4 sulfonic, octyldecylsulfuric, picric, benzoic, cinnamic, and like acids.
The acid-addition salts can be used for the same purposes as the free base or they can be employed to upgrade the same. For example, the free base can be converted to an insoluble salt, such as the picrate, which can be subjected to purification procedures, for example, solvent extractions and washings, chromatography, fractional liquid-liquid extractions, and crystallization and then used to regenerate the free base form by treatment with alkali or to make a different salt by metathesis. Or the free base can be converted to a water-soluble salt, such as the hydrochloride or sulfate and the aqueous solution of the salt extracted with various Water-immiscible solvents before regenerating the free base form by treatment of the thus-extracted acid solution or converted to another salt by metathesis. The free bases can be used as a buffer or as an antacid. They also react with isocyanates to form urethanes and can be used to modify polyurethane resins. The long chain compounds, i.e., where HR is alkyl of from 8 carbon atoms up, have surface active properties and can be used as wetting and emulsifying agents. The thiocyanic acid addition salt when condensed with formaldehyde forms resinous materials useful as inhibitors according to US. Pats. 2,425,320 and 2,606,155 in the acid pickling of steel. The free bases also make good vehicles for toxic acids. For example, the fluosilicic acid addition salts are useful as mothproofing agents according to US. Pats. 1,915,334 and 2,075,359, and the hexafluoroarsenic acid and hexafluorophosphoric acid addition salts are useful as parasiticides according to US Pats. 3,122,536 and 3,122,552.
The free bases also form salts with penicillins. These salts retain the antibacterial activity of the penicillins but have different solubility characteristics which make them useful in situations indicated by the special solubility characteristics and in the isolation and purification of the penicillins, particularly benzyl penicillin. Said salts can be formed either by neutralization of the free base form of a compound with the free acid form of a penicillin, or by a metathetical exchange of the anion of an acid "addition salt of the compound, for example, the chloride ion of a hydrochloride, with the anionic form of a penicillin.
The starting 7-halo-7-deoxy-lincomycins of Formula II can be prepared by reacting the corresponding lincomycin with thionyl chloride (Belgian Pat. 676,154) or with a Rydon reagent (Belgian Pat. 676,154).
The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting. Parts and percentages are by weight unless otherwise specified.
EXAMPLE 1 7 (S) -chlor0-7-deoxy-lincomycin-2-palmitate A1 3,4-O-ANISYLIDENE-7 (S) -CHLORO-7-DEOXY- LINCOMYCIN HYDROCHLORIDE A solution of 30 g. of 7(S')-chloro-7-deoxy-lincomycin in 60 ml. anisaldehyde and 50 ml. of dimethylformamide was warmed to 45 C. and then diluted with 200 ml. of benzene. The reaction mixture was set up for distillation and after collection of each ml. solvent an additional 100 ml. portion of fresh benzene was added. Crystallization slowly occurred during distillation. After collecting 1000 ml. of distillate by this process, ml. of benzene was added and the reaction mixture was allowed to cool to room temperature. The product was isolated by filtration and washed with acetone. The yield was 30 g. of white crystalline 3,4-O-anisylidene-7(S)- chloro-7-deoxy-lincomycin hydrochloride.
13-1 3,4O-ANIlSYLIDENE-7(S)-CHLORO-7-DE'OXY-LINCO- MYCIN-Z-LALMI'IATE HYDROCHLORIDE A partial solution of 23.18 g. of 3,4-O-anisylidene- 7(S)-chloro 7 deoxy-lincomycin hydrochloride in 200 ml. of pyridine and 40 ml. of chloroform was treated dropwise with a solution of 12.19 g. of palmitoyl chloride in 50 ml. chloroform over a 20 min. period. After 1 hr. at room temperature the clear orange reaction solution was concentrated to a viscous residue under high vacuum at 60 C. The residue was dissolved in 100 ml. isopropyl alcohol and the solvent was removed as above leaving a residue of 3,4-O-anisylidene 7(S)-chloro-7 deoxy-lincomycin-Z-palmitate hydrochloride.
C-l 7 S) -CHLORO-7-DEOXY-LINCOMYCINQ-PALMI- TATE HYDROCHLORIDE The residue of part Bl was dissolved in 200 m1. of acetic acid and diluted with 40 ml. of water. After heating on a steam bath at 90 C. for min., the solvents were removed under high vacuum at 60 C. The orange residue was dissolved in 100 ml. of isopropyl alcohol and the solvent was removed as before. The residue was dissolved in 150 ml. of acetone and the resulting solution was poured into 1500 ml. of acetonitrile to precipitate 7(S)- chloro 7 deoxy-lincomycin 2 palmitate hydrochloride. The compound was isolated by filtration under nitrogen and then' dried by slowly passing nitrogen through the filter for min. Final drying was achieved by drawing air through the filter cake for 1 hr. The yield was 23.5 g. (84%) of 7 (S)-chloro-7-deoxy-lincomycin-Z-palmitate hydrochloride, M.P. 126 (dec.).
Analysis.Calcd for C Hg N O SCl (percent): C, 58.35; H, 9.22; N, 4.00; S, 4.58; Cl, 10.13. Found (percent): C, 58.66; H, 9.30; N, 3.60; S, 4.23; CI, 10.82; H O, 0.76. (Analyses corrected for E 0 content.)
EXAMPLE 2 3,4-0-anisylidene 7(S)-chloro 7 deoxy-lincomycin- 2 laurate hydrochloride and 7(S) chloro 7 deoxylincomycin-Z-laurate hydrochloride EXAMPLE 3 3,4 0 anisylidene 7(S) chloro 7 deoxy lincomycin-Z-hexanoate hydrochloride and 7 (S)-chl0ro-7- deoxy-lincomycin-Z-hexanoate hydrochloride By substituting the palmitoyl chloride of part B-l by hexanoic acid anhydride, there was obtained 3,4-O-anisylidene 7(S) chloro 7 deoxy lincomycin-Z-hexanoate 4 which on hydrolysis by the procedure of part C-1 and recrystallization from hot water yielded 7(S)-chloro-7-deoxy lincomycin 2 hexanoate hydrochloride, M.P. 171-175-C.
Analysis.--Calcd for C H N 0 SCl (percent): C, 51.51; H, .7.93; N, 5.01; S, 5.73; Cl, 12.67. Found (percent): C, 5092; H, 8.14; N, 4.68; S, 5.77; CI, 12.45; H O, 2.4'1. (Analyses corrected for H O content.) I
EXAMPLE 4 3,4-0-(p-acetamidobenzylidene)-7(S)-chl0r07- deoxy-lincomycin hydrochloride A solution of 10 g. 7(S)-chloro-7-deoxy-lincomycin hydrochloride in 20 ml. dimethylformamide was mixed with a solution of g. p-acetamidobenzaldehyde in 150 ml. of benzene. The reaction mixture was set up for distillation and after collection of 50 ml. of distillate an additional 50 ml. of fresh benzene was added. A total of 500 ml. of benzene was collected by distillation.
The reaction vessel was cooled and a small amount of 7(S) chloro 7 deoxy lincomycin hydrochloride was removed by filtration. The filtrate was diluted with ;ether to precipitate 7.4 g. of 3,4-O-p-acetamidobenzylidene- 7(S)-chloro7-deoxy-lincornycin hydrochloride.
The compound was shaken with a mixture of. 50 ml. water and 10 ml. concentrated ammonium hydroxide. The resulting 3,4 O p acetamidobenzylidene 7 (S) chloro-7-deoxy-lincomycin base was isolated by filtration to give 5.2 g. of white compound.
This compound and other 3,4-'0-arylidine compounds as indicated above can be substituted for the 3,4-O-anisylide'ne-7 (S)-chloro 7 deoxy-lincomycin in the foregoing examples.
EXAMPLE 5 By substituting the 7(S)-chloro-7-deoxy-lincomycin of Examples 1, 2, and 3 by 7(S)-chloro-7-deoxy-N-carbobenzoxy-lincomycin there are obtained 3,4-'Oanisylidene- 7(S) chloro 7 deoxy N .carbobenzoxy-lincomycin, 3,4 O anisylidene 7 (S) chloro 7 deoxy N-carbobenzoxy-lincomycin-Z-palmitate, 2-laurate, and 2-hexanoate, 7(S)-chloro-7-deoxy-N-carbobenzoxy-lincomycin- 2 palmitate, 2 laurate, and 2 hexanoate. On removal of the carbobenzoxy group by hydrogenolysis over palladium on charcoal, there are obtained 7(S)-chloro-7-deoxy-'N-clemethyl-1incomyoin-2-palrnitate, 2-laurate, and 2- hexanoate. If desired, the hydrogenolysis can be effected to remove both the carbobenzoxy and the anisylidene groups. I
EXAMPLE 6 SCH; H
wherein Q is carbobenzoxy, there are obtained 3,4-O- anisylidene 7 chloro 6,7,8 trideoxy 6 (trans-1- carbobenzoxy 4 pentyl L 2 pyrrolidine-carboxamido) 1 thio L threo-a-D-galacto-octopyranoside and the Z-palmitate, 2-laurate, and 2-hexanoate esters thereof which on hydrolysis yield 7-ch1oro-6,7,8-trideoxy- 6 (trans 1 carbobenzoxy L Z-pyrroIidine-carboxamido) 1 thio L threo-a-D-galacto-octopyranoside- 2-palmitate, 2-laurate, and 2-hexanoate. On removal of the carbobenzoxy group by hydrogenolysis over palladium on charcoal, there are obtained 7-chloro-6,7,8-trideoxy- 6 (trans 4 pentyl L 2 pyrrolidine-carboxamido)- l thio L threo a-D-galacto-octopyranoside-Z-palmitate, 2-laurate, and 2-hexanoate. If desired, the hydrogenolysis can be effected before the hydrolysis in which case, the 3,4-O-arylidene group is also removed.
By substituting the 7(S)-chloro 7-deoxy-lincomycin hydrochloride in Examples 1, 2, and 3 by 7(S)-bromo-7- deoxy-lincomycin there are obtained the hydrochloride of 3,4 O arylidene-7(S) bromo-7-'deoxy-lincomycin and the 2-palmitate, 2-hexanoate thereof which esters on hydrolysis yield the hydrochloride of 7(S)-bromo-7-deoxylincomycin-Z-palmitate, 2-laurate, and 2-hexanoate.
By substituting the 7 (S) chloro 7 deoxy-lincomycin hydrochloride in Examples 1, 2, and 3 by 7 ('S)-brorno- 7 deoxy N carbobenzoxylincomycin, there are obtained 3,4 O anisylidene-7(S)-bromo-7-deoxy-N-carbobenzoxylincomycin and the 2-palmitate, the Z-Iaurate, and the Z-hexanoate thereof which esters on hydrolysis yield 7(S) bromo 7 deoxy N-carbobenzoxylincomycin-Z- palmitate, 2-laurate, and 2-hexanoate. On removal of the carbobenzoxy group by hydrogenolysis over palladium on charcoal, there are obtained 7(S)-bromo-7-deoxy-N- demethyllincomycin-Z-palmitate, Z-laurate, and 2-hexanoate. If desired, the hydrogenolysis can be effected without the hydrolysis in which case 7(S)-bromo-7-deoxy-N-demethyl-lineomycin-Z-palmitate, 2-laurate, and 2-hexan0ate is obtained directly.
By substituting the 7 (S) -chloroand bromo-7-deoxylincomycin hydrochlorides or the 7(S)-chloroandbromo-7-deoxy-N-carbobenzoxylincomycin by the 7-cpimers thereof, there are obtained the corresponding 7 (R)-compounds. The 7 (S)-epimcrs have the L-thco configuration in the side chain and the 7(R)-epirners have the D-erythro configuration in the side chain By substituting for anisaldehyde, the other aromatic aldehydes listed above, there are obtained the corresponding 3,4--arylidene compounds.
By substituting the acid chlorides and anhydrides, by the acid chlorides or anhydride of the other acids listed above, there are obtained the corresponding Z-acylates.
EXAMPLE 7 Syrup An aqueous oral preparation containing 400 mg. of 7(S) chloro 7 deoxy lincomycin-Z-palmitate hydrochloride in each five milliliters is prepared from the following ingredients:
Deionized water q.s., 10,000 ml.
The final preparation should be adjusted to pH 4.0-4.5.
We claim:
1. A pediatric formulation for controlling lincomycin susceptible bacterial infections in animals comprising water and an antibacterially effective amount of a compound of the formula:
or the salts thereof wherein X is chlorine, or bromine; R and HR; are the same or different alkyl of not more than 20 carbon atorn's,'cycloalkyl of from 3 to not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms; and R ishydrogen, alkyl of not more than 20 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl of not more than 12 carbon atoms, and
is alkanoyl of from 12 to not more than 18 carbon atoms. 2. A pediatric formulation according to claim 1 in which the compound is a compound of the formula:
or a salt thereof wherein is as given in claim 1. I
3. A pediatric formulation according to claim 2 in which 0 ll R1-C-' is palmitoyl.
4. A process for control of lincomycin susceptible bacteria in animals which comprises orally administering to said animal an antibacterially elfective amount of a compound of the formula:
or the salts thereof wherein X, R, HR
and R are as given in claim 1.
14 5. A process for control of bacteria in animals accordor a salt thereof wherein ing to claim 4 in which the compound is a compound of o the formula: Al
CH3 RI 5 is palmitoyl.
CH5 References Cited CSH7 U UNITED STATES PATENTS 6 3,282,918 11/1966 Hoeksema et a1. 26O----210 10 3,366,624 1/ 1968 Argoodelis et a1. 260210 0 H0 JEROME D. GOLDBERG, Primary Examiner SCH3 0 l5 ll
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Cited By (4)

* Cited by examiner, † Cited by third party
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US20050192236A1 (en) * 2001-08-28 2005-09-01 Chao Robert S. Crystaline clindamycin free base
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
EP2289512A1 (en) 2003-01-24 2011-03-02 Stiefel Research Australia Pty Ltd Pharmaceutical foam
US20110123631A1 (en) * 2008-07-22 2011-05-26 Kalpana Walzade Oral compositions of clindamycin

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050192236A1 (en) * 2001-08-28 2005-09-01 Chao Robert S. Crystaline clindamycin free base
EP2289512A1 (en) 2003-01-24 2011-03-02 Stiefel Research Australia Pty Ltd Pharmaceutical foam
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
US20110123631A1 (en) * 2008-07-22 2011-05-26 Kalpana Walzade Oral compositions of clindamycin
US9040089B2 (en) 2008-07-22 2015-05-26 Lupin Limited Oral compositions of clindamycin

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